Method and agent for the treatment and prophylaxis of diseases caused by (+)RNA-containing viruses

Abstract

The invention relates to medicine and concerns a method for the prophylaxis or treatment of diseases caused by (+)RNA-containing viruses which involves the use of an effective amount of glutaryl histamine or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition for the prophylaxis or treatment of diseases caused by (+)RNA-containing viruses which contains an effective amount of glutaryl histamine or a pharmaceutically acceptable salt thereof. The present invention solves the problem of providing a novel agent which is effective in the treatment of diseases caused by (+)RNA-containing viruses of the enterovirus genus or of the flavivirus genus.

Claims

1. A method for treating a disease caused by a (+)RNA-containing virus, the method comprising administering an effective amount of glutaryl histamine or a pharmaceutically acceptable salt thereof to a patient, wherein the (+)RNA-containing virus is selected from the group consisting of a rhinovirus, a coxsackie virus, a West Nile virus, a dengue fever virus, and a tick-borne encephalitis virus.

2. The method of claim 1, wherein the disease is an aggravation of asthma, chronic obstructive pulmonary disease, bronchitis, or mucoviscidosis, which is caused by a rhinovirus.

3. The method of claim 1, wherein the glutaryl histamine is administered in a solid dosage form.

4. The method of claim 1, wherein the glutaryl histamine or pharmaceutically acceptable salt thereof is administered in a total dosage amount of from 0.1 to 30 mg/kg of body weight of the patient.

5. The method of claim 1, wherein a daily dose of glutaryl histamine is 100 mg.

6. The method of claim 1, wherein duration of the glutaryl histamine administration is from 5 days to 12 months.

7. The method of claim 4, wherein the total dosage amount from 0.1 to 10 mg/kg of body weight of the patient.

8. The method of claim 1, wherein the glutaryl histamine or pharmaceutically acceptable salt thereof is administered in a dose of from 0.3 to 1.5 mg/kg of body weight of the patient, one or more times a day.

9. The method of claim 1, wherein the pharmaceutically acceptable salt is an alkali or alkaline-earth metal salt.

10. The method of claim 9, wherein the alkali or alkaline-earth metal salt is selected from the group consisting of a sodium salt, a potassium salt, and a lithium salt.

Description

DESCRIPTION OF THE INVENTION

(1) The inventors have unexpectedly found that glutaryl histamine can be used as a non-toxic antiviral agent against infections caused by viruses belonging to, but not limited to, the Enterovirus and Flavivirus genera.

(2) In view of the above, the present invention relates to an agent for the treatment and/or prevention of diseases caused by (+)RNA-containing viruses belonging to the Enterovirus genus or the Flavivirus genus, wherein the agent is glutaryl histamine of the following formula:

(3) ##STR00001##

(4) Glutaryl histamine according to the invention is administered in a solid dosage form.

(5) The invention also relates to a method for the prevention and treatment of diseases caused by (+)RNA-containing viruses belonging to the Enterovirus genus or the Flavivirus genus, the method comprising administering an effective amount of glutaryl histamine or a pharmaceutically acceptable salt thereof to a patient.

(6) The virus belonging to the Enterovirus genus can be selected from the group including rhinoviruses, Coxsackie viruses and enterovirus type 71. The virus belonging to the Flavivirus genus can be selected from the group including West Nile virus, dengue virus, tick-borne encephalitis virus, Saint-Louis encephalitis virus, Murray Valley encephalitis virus, and yellow fever virus. A dose of glutaryl histamine or a pharmaceutically acceptable salt thereof can be from 0.1 to 30 mg/kg of patient's body weight. A single dose of glutaryl histamine can be about 100 mg. A preferable duration of the administration of glutaryl histamine can be from 5 days to 12 months. One embodiment of the invention relates to the prevention or treatment of aggravations of asthma, chronic obstructive pulmonary disease, bronchitis and mucoviscidosis, which are caused by rhinoviruses.

(7) Further, the invention relates to a pharmaceutical composition for the treatment of diseases caused by (+)RNA-containing viruses belonging to the Enterovirus genus or the Flavivirus genus, wherein the composition comprises an effective amount of glutaryl histamine or a pharmaceutically acceptable salt thereof. The effective amount of glutaryl histamine or a pharmaceutically acceptable salt thereof is preferably from 0.1 to 30 mg/kg of patient's body weight. A dose of glutaryl histamine can be 100 mg in once-daily administration.

(8) The invention also relates to a kit for the treatment of diseases caused by (+)RNA-containing viruses belonging to the Enterovirus genus or the Flavivirus genus, wherein the kit includes the composition according to the invention and instructions for use thereof.

(9) In addition, the invention relates to use of glutaryl histamine or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the treatment of diseases caused by (+)RNA-containing viruses belonging to the Enterovirus genus or the Flavivirus genus. The invention also relates to use of glutaryl histamine or a pharmaceutically acceptable salt thereof for the treatment of diseases caused by (+)RNA-containing viruses belonging to the Enterovirus genus or the Flavivirus genus.

(10) Pharmaceutically acceptable salts of glutaryl histamine according to the invention can be alkali or alkaline-earth metals salts thereof, preferably sodium, potassium, and lithium salts.

(11) Glutaryl histamine or salts thereof are administered in an effective amount to provide a desired therapeutic result.

(12) Glutaryl histamine or salts thereof can be administered to a patient in a dose of from 0.1 to 30 mg/kg of human body weight, preferably in a dose of from 0.3 to 1.5 mg/kg, one or more times a day.

(13) It should be noted that a particular dose for each particular patient depends on many factors, such as patient's age, body weight, gender, general health condition, and diet; the schedule and route of the administration of the agent and its excretion rate from the body; and disease severity in treated patients.

(14) The pharmaceutical compositions according to the invention comprise glutaryl histamine or a pharmaceutically acceptable salt thereof in an amount effective to provide a desired result, and can be prepared in unit dosage forms (for example, in solid, semi-solid, or liquid forms) which comprise glutaryl histamine or a salt thereof as an active agent in a mixture with a carrier or an excipient suitable for intramuscular, intravenous, oral, sublingual, inhalation, intranasal, rectal, and transdermal administration. The active agent can be added to the composition together with conventional nontoxic pharmaceutically acceptable carriers suitable for the manufacture of solutions, tablets, pills, capsules, pellets, suppositories, emulsions, suspensions, ointments, gels, patches, and any other dosage forms.

(15) Various compounds can be used as excipients, such as saccharides, for example, glucose, lactose or sucrose; mannitol or sorbitol; cellulose derivatives; and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrophosphate. The following compounds can be used as a binder: starch paste, for example, corn, wheat, rice, or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone. Disintegrating agents can be optionally used, such as the aforementioned starches and carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar-agar, or alginic acid or a salt thereof, such as sodium alginate.

(16) Optional additives, such as flow control agents and lubricating agents, for example, silica, talc, stearic acid and salts thereof, for example, magnesium stearate or calcium stearate, and/or propylene glycol, are also can be used.

(17) Stabilizing agents, thickening agents, colorants, and flavoring agents also can be used as additives.

(18) An ointment base can be selected from hydrocarbon ointment bases, such as white Vaseline and yellow Vaseline (Vaselinum album and Vaselinum flavum, respectively), Vaseline oil (Oleum Vaselini), and white ointment and liquid ointment (Unguentum album and Unguentum flavum, respectively), wherein solid paraffin and wax can be used as a thickening additive. Absorptive ointment bases, such as hydrophilic Vaseline (Vaselinum hydrophylicum), lanoline (Lanolinum), and cold cream (Unguentum leniens); water-removable ointment bases, such as hydrophilic ointment (Unguentum hydrophylum); and water-soluble ointment bases, such as polyethylene glycol ointment (Unguentum Glycolis Polyaethyleni); bentonite bases; and others are also suitable.

(19) Methylcellulose, sodium carboxymethylcellulose, oxypropylcellulose, polyethylene glycol or polyethylene oxide, and carbopol are useful as a base for gels.

(20) Water-insoluble bases such as cocoa butter; water-soluble or water-miscible bases, such as gelatin-glycerol or polyethylene oxide bases; and combination (soap-glycerol) bases are useful as a base for suppositories.

(21) In a unit dosage form, the amount of an active agent used in combination with a carrier can vary depending on a patient to be treated and a particular route of administration of a therapeutic agent.

(22) For example, when glutaryl histamine or a salt thereof is used in the form of a solution for injections, the active agent in the solution is in an amount of 0.1 to 5%. Suitable diluents are 0.9% sodium chloride solution, distilled water, Novocain solution for injections, Ringer solution, glucose solution, and specific solubilizing additives. When glutaryl histamine or a salt thereof is administered in the form of tablets or suppositories, its amount ranges 10 to 300 mg per unit dosage form.

(23) Dosage forms according to the invention are produced by standard methods, such as blending, granulation, forming pellets, dissolution, and lyophylization.

(24) It should be noted that no adverse side effects have been registered during long-term administration of glutaryl histamine or a salt thereof in therapeutic doses or doses which are greater by an order of magnitude than therapeutic ones.

EMBODIMENT OF THE INVENTION

(25) The following examples disclose the invention in more details to demonstrate the effectiveness of glutaryl histamine for the prevention and treatment of diseases according to the present invention, where the disclosed examples are not intended to limit the scope of the invention.

Example 1

Antiviral Activity of Glutaryl Histamine Against a Human Rhinovirus on an In Vivo Experimental Model

(26) The study was performed with a human rhinovirus strain (HRV 1B) preliminarily adapted to the proliferation in the mouse lungs.

(27) Specificity of HRV was controlled by a polymerase chain reaction (PCR), Real-time PCR (AmpliSense, Russia) and two-round PCR with primers specific for RNA derived from the suspension of lungs and trachea of HRV-infected mice by using “Ribo-sorb” kit manufactured by “AmpliSense”.

(28) White Balb/c male mice weighed from 8 to 10 g were infected with virus-containing material in an amount of 0.05 ml/mouse intranasally under brief ether anesthesia.

(29) The mice were handled according to the Guidelines for the Care and Use of Laboratory Animals. Before the study, the animals were quarantined for five days.

(30) The animals were provided with standard food ration and kept under the same conditions. Mice were divided into groups of 10 animals each.

(31) Glutaryl histamine was administered orally once daily for 3 days, starting at 12 hours after infection of the mice with HRV. Mice of the control group were administered normal saline under the same conditions.

(32) Glutaryl histamine was administered in doses 15 and 30 mg/kg.

(33) HRV infection titers in suspensions of mouse trachea and lungs 48 and 72 hours after infection were determined by individual analysis of 10% suspension derived from each mouse in a series of 10-fold dilutions on cell culture Hela. Results were assessed by PCR at 2 hours after incubation at 33° C.

(34) Each dilution of a test probe was assessed in four wells of a plate, and the obtained values were used to calculate a mean value. The maximum dilution of infected culture supernatant wherein the viral RNA was detected by PCR was accepted as a virus titer. The titer was expressed as the reciprocal value of the virus dilution in which HRV RNA was determined (lg/ml is represented as a mean value: lg±m).

(35) Statistic analysis of the results was performed using Microsoft Excel software.

(36) The effectiveness of glutaryl histamine was evaluated by the suppression of the virus reproduction in lungs at 48 and 72 hours after HRV infection.

(37) Criteria of the in vivo glutaryl histamine effectiveness were a reduction in the accumulation of virus in lungs, determined based on infectious titer in the cell culture Hela and directly in suspensions of mouse lungs by a PCR method.

(38) Results of the determination of the infectious activity of HVR in suspensions of mouse lungs in the cell culture Hela are given in Table 1.

(39) Titration of lung suspensions of the HVR infected mice showed proliferation of the virus in the lungs, which reached the maximum value of 4.1 lg in 48 hours, and 3.2 lg in 72 hours in the control group. The use of glutaryl histamine led to a quite pronounced reduction in the infectious activity of HRV, in particular by 2.6 and 2.2 lg, respectively, in a used dose of glutaryl histamine of 30 mg/kg.

(40) The same results were obtained in studying the effectiveness of glutaryl histamine against HVR infection in mice by the suppression and activity of the virus directly in lungs by a PCR method. Real time PCR demonstrated a significant reduction in the amount of viral RNA copies at 48 and 72 hours after infection, namely from 10 to 100 times, in the group of mice administered glutaryl histamine, compared to the control groups.

(41) Thus, this example shows a possibility of using glutaryl histamine as an effective antiviral agent which specifically decreases the reproduction of the human rhinovirus.

(42) TABLE-US-00001 TABLE 1 Infectious titer of the HVR virus in the mouse lungs in 48 and 72 hours Total Infectious amount of virus Suppression animals in titer in of the virus each group lungs, lg, reproduction Drug (n) TCID.sub.50 (Δ lg) P Glutaryl 10 2.8 ± 0.4 1.3 0.01 histamine, 15 mg/ml (48 hrs) Glutaryl 10 1.5 ± 0.3 2.6 0.001 histamine, 30 mg/ml (48 hrs) Normal saline 4.1 ± 0.4 (48 hrs) Glutaryl 10 2.1 ± 0.3 1.1 histamine, 15 mg/ml (72 hrs) Glutaryl 10 1.0 ± 0.3 2.2 0.01 histamine, 30 mg/ml (72 hrs) Normal saline 10 3.2 ± 0.4 (72 hrs)

Example 2

Study of the Effectiveness of Glutaryl Histamine Against an Experimental Form of West Nile Fever (WNF)

(43) In the experiment West Nile virus strain Eg101 was used. Infected animals were monitored for 21 days. Their death was controlled, and the average lifetime of the white mice were calculated in the experimental and control groups.

(44) The main criteria of the in vivo effectiveness were the values of protection of the laboratory animals against death and the average lifetime of the animals in a group.

(45) To estimate the effectiveness of glutaryl histamine, white mice were infected subcutaneously with a dose of 10LD.sub.50. Glutaryl histamine was administered orally according to the following schemes: for prevention—in a dose of 5 mg/kg, once daily for 4 days before infection and at 1 hour before infection; in a dose of 30 mg/kg, once weekly; for treatment—in a dose of 5 mg/kg, at 24 after infection and then for 7 days; in a dose of 30 mg/kg, once daily at 24 and 48 hours after infection, then a single dose of 15 mg/kg in 72, 96 and 120 hours.

(46) Results of the evaluation of the effectiveness given in Table 2 demonstrate that glutaryl histamine protects infected mice against death when administered in a dose of 5 mg/kg by the prevention and treatment schemes. The protection against death was 42.9% and 37.8%, respectively. In addition, the average lifetime of the animals in the groups significantly increased (by 4.2 and 2.8 days, respectively).

(47) TABLE-US-00002 TABLE 2 Results of the study of the glutaryl histamine effectiveness on the experimental model of West Nile Fever in white mice Extension of the Average average Protective lifetime, lifetime, Drug Scheme ratio, % days Δ, days Glutaryl −96 h, −72 h, −48 h, 42.9 11.2 4.2 histamine −24 h, −1 h +24 h, +48 h, +72 h, +96 h, +120 h, +144 37.8 9.8 2.8 h, +168 h Control of a virus dose (without — 7.0 — drug) Control of a herd — 21.0 —

(48) In the second therapeutic scheme (Table 3), the protective effectiveness of glutaryl histamine in a dose of 30 mg/kg on the experimental model of West Nile Fever in white mice in a single administration at 144 hours before infection was 40.0% and an increase in the average lifetime of the animals was 3.7 days.

(49) TABLE-US-00003 TABLE 3 Results of the study of the glutaryl histamine effectiveness on the experimental model of West Nile Fever in white mice in a single administration before infection Extension of Average the average lifetime of lifetime of Drug Drug Protection animals in animals in a dose, administration against a group, group, Δ, Drug mg/kg scheme death, % days days Glutaryl 30 −144 h 40.0 10.8 3.7 histamine Control of a virus dose (without — 7.1 — drug) Control of a herd 21.0

(50) Results of the evaluation of the effectiveness given in Table 4 demonstrate that the agent effectively protects the infected mice against death in administration thereof by the treatment scheme (30 mg/kg once daily for 2 days, then 15 mg/kg once daily for 3 days). The protection against death was 50.0% and the average lifetime of the animals in the group increased by 3.5 days. The reference medicament ribavirin protected against death 50% of animals when administered by the prevention scheme in a dose of 20 mg/kg. It should be noted that the protective effectiveness of ribavirin in the administration thereof by the treatment scheme was 10.0%.

(51) Thus, in the experimental form of West Nile Fever (WNF), glutaryl histamine effectively protected the infected animals against death.

(52) TABLE-US-00004 TABLE 4 Results of the glutaryl histamine effectiveness in the experimental form of West Nile Fever in white mice Extension of Average the average lifetime of lifetime of Drug Drug Protection animals in animals in a dose, administration against a group, group, Δ, Drug mg/kg scheme death, % days days Glutaryl 30/15 +24 h, +48 h, 50.0 11.5 4.5 histamine +72 h, +96 h, Ribavirin 20 +120 h 10.0 7.2 0.2 Control virus dose (without drug) — 7.0 — Control of a herd 21.0

Example 3

Study of the Glutaryl Histamine Effectiveness on an Experimental Model of a Tick-Borne Encephalitis Virus (TBE)

(53) The glutaryl histamine effectiveness was studied on the experimental model of TBE in white mice weighed from 9 to 10 g which were infected subcutaneously with TBE virus strain Sof′ in in a dose of 30LD.sub.50. Glutaryl histamine was administered orally in a dose of 5 mg/kg by the prevention scheme (at 5 days before infection, once daily); by the prevention/treatment scheme (at 5 days before infection and for 7 days after infection, once daily); by the treatment scheme (at 24 hours after infection and then for 7 days, once daily); as well as in a dose of 30 mg/ml, by the prevention scheme (once a week); by the treatment scheme (once daily at 24 and 48 hours after infection, then in a single dose of 15 mg/kg in 72, 96 and 120 hours).

(54) Ribavirin was used as a reference medicament by the emergency prevention scheme in a dose of 20 mg/kg.

(55) Results of the studies given in Table 5 demonstrate that the maximum antiviral effectiveness of glutaryl histamine was observed when glutaryl histamine was administered by the prevention and prevention/treatment schemes. It was showed that protection against death was 40% and an increase in the average lifetime was 4.2 days. In the administration by the prevention and prevention/treatment schemes, the protective effectiveness of glutaryl histamine was 35%.

(56) TABLE-US-00005 TABLE 5 Results of the study of the glutaryl histamine effectiveness on the experimental model of TBE in white mice Extension of the Average average Drug administration lifetime, lifetime, Protective Drug scheme days Δ, days ratio, % Glutaryl −96 h, −72 h, −48 h, −24 15.1 3.9 35.0 histamine h, −1 h −120 h, −96 h, −72 h, 15.4 4.2 40.0 −48 h, −24 h, +1 h, +24 h, +48 h, +72 h, +96 h, +120 h, +144 h +1 h, +24 h, +48 h, +72 13.6 2.4 35.0 h, +96 h, +120 h, +144 h Ribavirin +1 h, +24 h, +48 h, +72 15.0 3.8 35.0 h, +96 h, +120 h, +144 h Control of 11.2 a virus dose (without drug) Control of 21.0 — — a herd “−”—the administration of a medicament before infection; “+”—the administration of a medicament after infection.

(57) In the second prevention scheme (Table 6), the protective effectiveness of glutaryl histamine in a dose of 30 mg/kg on the experimental model of tick-borne encephalitis in white mice in a single administration at 144 hours before infection was 30.0% and an increase in the average lifetime of the animals was 3.1 days.

(58) TABLE-US-00006 TABLE 6 Results of the evaluation of the glutaryl histamine effectiveness on the experimental model of tick-borne encephalitis in white mice in a single administration in a dose of 30 mg/kg before infection Extension of the Drug Average average Protection administration lifetime, lifetime, against Drug scheme days days death, % Glutaryl −144 h 10.5 3.1 30.0 histamine Control of a virus dose (without 7.4 drug) Control of a herd 21.0

(59) Results of the evaluation of the effectiveness given in Table 7 demonstrate that the glutaryl histamine effectively protects the infected mice against death in administration thereof by the treatment scheme (30 mg/kg once daily for 2 days, then 15 mg/kg once daily for 3 days). Protection against death was 40.0% and the average lifetime of the animals in the group increased by 3.2 days. It should be noted that the protective effectiveness of ribavirin when administered by the treatment scheme was 15.0%.

(60) Thus, in the experimental model of tick-borne encephalitis, glutaryl histamine effectively protects the infected animals against death.

(61) TABLE-US-00007 TABLE 7 Results of the evaluation of the glutaryl histamine effectiveness on the experimental model of tick-borne encephalitis in white mice administered with a dose of 30/15 mg/kg Extension of the Drug Average average Protection administration lifetime, lifetime, against Drug scheme days days death, % Glutaryl +24 h, +48 h, 10.1 3.2 40.0 histamine +72 h, +96 h, Ribavirin +120 h 7.2 0.3 15.0 Control of a virus dose 6.9 (without drug) Control of a herd 21.0

Example 4

Study of the Effectiveness of Glutaryl Histamine in Experimental Form of Dengue Fever

(62) To determine antiviral activity, white mice were infected intracerebrally with a dengue fever virus. Glutaryl histamine was administered orally by the following schemes: for prevention—in a dose of 5 mg/kg, once daily for 4 days before infection and at 1 hour before infection; in a dose of 30 mg/kg, once weekly; for treatment—in a dose of 5 mg/kg, at 24 after infection and then for 7 days; in a dose of 30 mg/kg, once daily in 24 and 48 hours, then in a dose of 15 mg/kg once daily at 72, and 120 hours after infection. Infected animals were monitored for 21 days. Biological samples were evaluated on day 5 after infection.

(63) Results of the effectiveness evaluation given in Table 8 demonstrate that glutaryl histamine inhibits effectively the proliferation of the dengue hemorrhagic fever virus in the mice blood when administered by the prevention and treatment schemes in a dose of 5 mg/kg. The level of inhibition of the virus accumulation was 95.5%.

(64) TABLE-US-00008 TABLE 8 Results of the study of the effectiveness of inhibition of the dengue fever virus proliferation in the blood of white mice infected intracerebrally with a dose of 5 mg/kg, obtained on the experimental form of dengue fever Level of virus Reduction in Degree of accumulation the level of inhibition of in the virus the virus blood, lg accumulation, accumulation, Drug Scheme PFU/ml lg % Glutaryl −96 h, −72 h, −48 5.0 1.6 95.5 histamine h, −24 h, −1 h +24 h, +48 h, +72 4.8 1.8 98.6 h, +96 h, +120 h, +144 h, +168 h Control of a virus dose 6.6 (without drug)

(65) Results of the evaluation of the effectiveness given in Table 9 demonstrate that glutaryl histamine effectively inhibits the proliferation of the dengue hemorrhagic fever virus in the blood of white mice when administered by the treatment scheme (30 mg/kg once daily for 2 days, then 15 mg/kg once daily for 3 days). The level of inhibition of the virus accumulation was 99.6%. It should be noted that in the treatment scheme the level of inhibition of the virus accumulation in the blood of the animals treated with ribavirin was only 83.4%.

(66) Thus, in case of dengue hemorrhagic fever, glutaryl histamine effectively inhibits the virus replication in infected animals.

(67) TABLE-US-00009 TABLE 9 Results of the study of the effectiveness of inhibition of the dengue hemorrhagic fever virus proliferation in the blood of white mice infected intracerebrally with a dose of 30/15 mg/kg, obtain on the experimental form of dengue hemorrhagic fever Level of Reduction in Degree of virus the level of inhibition of accumulation virus the virus in the blood, accumulation, accumulation, Drug Scheme lg PFU/ml lg % Glutaryl +24 h, +48 h, 4.8 2.6 99.6 histamine +72 h, +96 h, Ribavirin +120 h 6.4 1.0 83.4 Control of a virus dose 7.4 (without drug)

Example 5

Antiviral Effect of Glutaryl Histamine Against a Coxsackie Virus

(68) In the study, a trypsin-dependent strain HCXV was used that was previously adapted and caused death of Coxsackie virus-infected mice.

(69) The experiment was carried out on white mice weighed 6 to 7 g.

(70) The animals were infected intramuscularly in a dose of 0.1 ml/mouse. The dose used in the experiment was 10LD.sub.50 which caused 70-80% lethality in mice.

(71) The therapeutic capability of glutaryl histamine was evaluated by a mortality rate in the HCXV virus-infected mice in the test group compared with the group of untreated mice.

(72) The test drugs and placebo were administered orally by the treatment scheme. Normal saline solution was administered to mice as placebo. 14 intact animals that were kept in a separate room under the same conditions as the experimental animals were used as a negative control.

(73) The experiment was conducted on 4 groups by 14 animals. The animals of the first, second and the third groups were administered glutaryl histamine in a dose of 30 mg/kg, 3 mg/kg, and 0.3 mg/kg of body weight, respectively, and the animals of the fourth control group were received a normal saline solution. The drugs were administered orally once daily for 5 days (first administration—at 24 hours after the infection). The animals were monitored for 20 days, during which the animals were weighed every day, and the mortality rate was registered.

(74) During the study the glutaryl histamine effectiveness in HCXV virus-infected animals, none of non-specific fatal cases were registered in the control group of intact animals.

(75) TABLE-US-00010 TABLE 10 Protective effectiveness of glutaryl histamine against an HCXV virus Extension Total of the Dose of number of Total Average days Protective glutaryl animals in mortality lifetime, lifetime, ratio, % histamine a group (n) rate (%) Δ, days average 30 mg/kg 14 57.1 19.6 +9.6 27.4  3 mg/kg 14 50.0 21.7 +11.7 36.4 0.3 14 42.9 24.4 +14.4 45.4 mg/kg Virus 14 78.6 10.0

(76) Results of the study demonstrate that first fatal cases in the group of virus-infected mice, which were not administered glutaryl histamine, were registered on day 7 after the infection, and 78.6% of the mice died up to day 9. The average lifetime in the control group was 10.0 days.

(77) Glutaryl histamine demonstrate a statistically significant protective effect against the experimental model of infection with the Coxsackie virus, expressed in a decrease of the mortality rate among the animals and in an increase in the average lifetime of the animals.

(78) A high antiviral activity of glutaryl histamine described in this example evidences that this agent is useful as an effective drug in the treatment of HCXV enterovirus infections.

Example 6

The Manufacture of Dosage Forms of Glutaryl Histamine

(79) Dosage forms of glutaryl histamine used according to the present invention are prepared by standard methods such as, for example, processes of mixing, granulating, forming pills, dissolving and lyophilizing.

(80) Tableted Form

(81) A tableted form is prepared by using the following ingredients:

(82) TABLE-US-00011 Glutaryl histamine or a from 1 to 100 mg pharmaceutically acceptable salt thereof Potato starch from 20 to 50 mg Magnesium stearate from 3 mg Aerosil 1 mg Lactose up to 300 mg

(83) The ingredients are mixed and compressed to form tablets weighing 300 mg

(84) TABLE-US-00012 Gelatinous capsules Glutaryl histamine or a 90 mg pharmaceutically acceptable salt thereof Lactose (milk sugar), potato up to 220 mg in starch, colloidal silica (Aerosil), capsule magnesium stearate

(85) The above-mentioned ingredients are mixed and granulated, and the resulting granules are placed into solid gelatinous capsules in an amount of 220 mg.

(86) TABLE-US-00013 Suppositories Example of the formulation of a suppository Glutaryl histamine or a from 1 to 100 mg pharmaceutically acceptable salt thereof Cacao oil in an amount required for a suppository

(87) Rectal, vaginal, and urethral suppositories can be optionally prepared by using corresponding excipients.

(88) Solution for Injections

(89) Example 1 of the formulation of a solution for injections:

(90) TABLE-US-00014 Glutaryl histamine or a from 1 to 100 mg pharmaceutically acceptable salt thereof Water for injections 2 ml

(91) A solution for injections can be prepared by using 0.9% sodium chloride solution, distilled water and a Novocain solution, as a diluent. Pharmaceutical forms include ampules, flasks, syringe-tubes, and “inserts”.

(92) Formulation 1 of a solution for injections:

(93) TABLE-US-00015 Glutaryl histamine or a salt 100 mg thereof Distilled water 5 ml

(94) A solution for injections can be prepared by using 0.9% sodium chloride solution, isotonic phosphate buffer, or HEPES, as a diluent. Pharmaceutical forms include ampules, flasks, syringe-tubes, and “inserts”.

(95) Formulations for injections can be prepared in various dosage units such as sterile solution, sterile powders, and tablets.